Biomarkers for personalised prevention of chronic diseases: a common protocol for three rapid scoping reviews.

INTRODUCTION: Personalised prevention aims to delay or avoid disease occurrence, progression, and recurrence of disease through the adoption of targeted interventions that consider the individual biological, including genetic data, environmental and behavioural characteristics, as well as the socio-cultural context. This protocol summarises the main features of a rapid scoping review to show the research landscape on biomarkers or a combination of biomarkers that may help to better identify subgroups of individuals with different risks of developing specific diseases in which specific preventive strategies could have an impact on clinical outcomes. This review is part of the "Personalised Prevention Roadmap for the future HEalThcare" (PROPHET) project, which seeks to highlight the gaps in current personalised preventive approaches, in order to develop a Strategic Research and Innovation Agenda for the European Union. OBJECTIVE: To systematically map and review the evidence of biomarkers that are available or under development in cancer, cardiovascular and neurodegenerative diseases that are or can be used for personalised prevention in the general population, in clinical or public health settings. METHODS: Three rapid scoping reviews are being conducted in parallel (February-June 2023), based on a common framework with some adjustments to suit each specific condition (cancer, cardiovascular or neurodegenerative diseases). Medline and Embase will be searched to identify publications between 2020 and 2023. To shorten the time frames, 10% of the papers will undergo screening by two reviewers and only English-language papers will be considered. The following information will be extracted by two reviewers from all the publications selected for inclusion: source type, citation details, country, inclusion/exclusion criteria (population, concept, context, type of evidence source), study methods, and key findings relevant to the review question/s. The selection criteria and the extraction sheet will be pre-tested. Relevant biomarkers for risk prediction and stratification will be recorded. Results will be presented graphically using an evidence map. INCLUSION CRITERIA: Population: general adult populations or adults from specific pre-defined high-risk subgroups; concept: all studies focusing on molecular, cellular, physiological, or imaging biomarkers used for individualised primary or secondary prevention of the diseases of interest; context: clinical or public health settings. SYSTEMATIC REVIEW REGISTRATION: https://doi.org/10.17605/OSF.IO/7JRWD (OSF registration DOI).

Long-term impact of the 2008 economic crisis in Spain on road traffic collisions mortality by socioeconomic position.

We aimed to assess the effect of the 2008 crisis on road traffic collision (RTC) mortality in Spain, by socioeconomic position (SEP) and type of road use. This prospective, country-wide study covered all adults living in Spain and aged ≥30 years in November 2001. The long-term effect of the crisis was assessed by measuring the monthly percentage change (MPC) in RTC mortality between the pre-crisis (2002-2007) and crisis period (2008-2011). During the recession, RTC mortality fell more in people with low compared to high SEP, so MPCs difference between periods were of a higher magnitude in the low compared to high SEP groups, especially among men motorcyclists. RTC mortality trends were favorable following the 2008 crisis, particularly among low-SEP groups. In men motorcyclists, the upward trend of the pre-crisis period reversed course.

Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data.

Designing public health responses to outbreaks requires close monitoring of population-level health indicators in real-time. Thus, an accurate estimation of the epidemic curve is critical. We propose an approach to reconstruct epidemic curves in near real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We address two data collection problems that affected the reliability of the available real-time epidemiological data, namely, the frequent missing information documenting when a patient first experienced symptoms, and the frequent retrospective revision of historical information (including right censoring). This is done by using a novel back-calculating procedure based on imputing patients' dates of symptom onset from reported cases, according to a dynamically-estimated "backward" reporting delay conditional distribution, and adjusting for right censoring using an existing package, NobBS , to estimate in real time (nowcast) cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number ( R t ) in real-time. At each step, we evaluate how different assumptions affect the recovered epidemiological events and compare the proposed approach to the alternative procedure of merely using curves of case counts, by report day, to characterize the time-evolution of the outbreak. Finally, we assess how these real-time estimates compare with subsequently documented epidemiological information that is considered more reliable and complete that became available later in time. Our approach may help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health surveillance systems in other locations.

Association between heavy metals and metalloids in topsoil and mental health in the adult population of Spain.

BACKGROUND AND OBJECTIVES: Despite the biological plausibility of the association between heavy metal exposure and mental health disorders, epidemiological evidence remains scarce. The objective was to estimate the association between heavy metals and metalloids in soil and the prevalence of mental disorders in the adult population of Spain. METHODS: Individual data came from the Spanish National Health Survey 2011-2012, 18,073 individuals residing in 1772 census sections. Mental health was measured with the 12-item General Health Questionnaire. The concentration estimates of heavy metal and metalloid levels in topsoil (upper soil horizon) came from the Geochemical Atlas of Spain based on 13,317 soil samples. Levels of lead (Pb), arsenic (As), cadmium (Cd) and manganese (Mn) were estimated in each census section by "ordinary Kriging". Odds ratios (OR) were calculated by multilevel logistic regression models. RESULTS: Compared with the lowest Pb concentration levels quartile, the OR for the second quartile was 1.29 (95%CI: 1.11-1.50), increasing progressively to 1.37 (95%CI: 1.17-1.60) and 1.51 (95%CI: 1.27-1.79) in the third and fourth quartiles, respectively. For As, the association was observed in the third and fourth quartiles: 1.21 (95%CI: 1.04-1.41) and 1.42 (95% CI: 1.21-1.65), respectively. Cd was associated also following a gradient from the second quartile: 1.34 (95%CI: 1.15-1.57) through the fourth: 1.84 (95%CI: 1.56-2.15). In contrast, Mn only showed a positive association at the second quartile. Additionally, individuals consuming vegetables > once a day the OR for the fourth quartile of Pb concentration, vs. the first, increased to 2.93 (95%CI: 1.97-4.36); similarly for As: 3.00 (95%CI: 2.08-4.31), and for Cd: 3.49 (95%CI: 2.33-5.22). CONCLUSIONS: Living in areas with a higher concentration of heavy metals and metalloids in soil was associated with an increased probability of having a mental disorder. These relationships were strengthened in individuals reporting consuming vegetables > once a day.

Suicide mortality trends in Galicia, Spain and their relationship with economic indicators.

BACKGROUND: Recent research has shown an association between unemployment and suicide, but the mediating factors in this relationship are still unknown. In this study, we investigated the effect of unemployment and economic recession on suicide rates in the Spanish region of Galicia between 1975 and 2012 Method. We analysed age-standardised suicide rates in men and women and in four age groups: less than 25 years, 25-45 years, 45-65 years and more than 65 years and performed a joinpoint analysis to determine trend changes throughout 1975-2012 period. Also we analysed the association between suicide, recession and unemployment by means of a temporal trend model with a Generalised Additive Model. RESULTS: Suicide rates increased from 145 suicides in 1975 to a high in 1993, with 377 deaths by suicide, representing 1.38% of all causes of death, and thereafter they tend to decrease to 335 suicides in 2012. Joinpoint analyses revealed that suicide rates changed differently across sex and age groups. For men, the annual percentage of change (APC) between 1975 and 1988 (CI 95% 1986-1994) was 5.45 (CI 95% = 3.5, -7.2) but from 1988 the APC became negative [-0.66 (CI 95% = -1.3, -0.1)]. For women, APC between 1974 and 1990 (CI 95% 1986-1992) was 4.86 (CI 95% = 3.2, -6.4) and -1.46 subsequently (CI 95% = -2.2, -0.5). Women aged 24 years or less showed stable suicide rates while men from 45-65 years showed two incidence peaks. When we studied the independent correlation between unemployment, recession and suicide, we found a significant association between unemployment and suicide, but not between recession and suicide for both sexes together and for men while for women there was no significant correlation between suicide and unemployment or recession. Finally, when we studied the effect of the interaction between unemployment and recession on suicide we found economic recession and unemployment interacted with regards to suicide rates (F = 5.902; df = 4.167; p = 0.00098) and after adjusting by sex, the effect was confirmed among men (F = 4.827; df = 2.823; p = 0.0087), but not among women (F = 0.001; df = 1.000; p = 0.979). CONCLUSIONS: Although suicide rates in Galicia are gradually decreasing in the last decades, there are important sex and age differences. Unemployment was related with suicide during economic recession periods according to our results.

Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development.

The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in γ2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected γ2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.

The stromal gene encoding the CD274 antigen as a genetic modifier controlling survival of mice with γ-radiation-induced T-cell lymphoblastic lymphomas.

Using an inter-specific subcongenic strain, Nested Recombinant Haplotype 3 (NRH3), generated between two mouse strains showing extreme differences in γ-radiation-induced thymic lymphoma susceptibility (SEG/Pas and C57BL/6J), we have identified a critical region on chromosome 19 that regulates survival of mice suffering from T-cell lymphoblastic lymphomas. Mapped on this region, the gene encoding the Cd274 ligand is able to trigger an inhibitory effect that modulates T-cell receptor (TCR) signalling and affects thymocyte maturation. Interestingly, this gene shows differential expression between thymic stromal cells from both strains in early response to a single sublethal γ-ray dose, but is inhibited in T-cell lymphoblastic lymphomas. Furthermore, we have identified several polymorphisms in the complementary DNA sequence of this gene that affect the affinity for its Cd279 receptor and are able to induce a differential rate of thymocyte apoptosis. Taken together, our data are consistent with Cd274 acting as a genetic modifier that influences the survival of γ-radiation-induced T-cell lymphoma-bearing mice. The data similarly support the idea of a co-evolution of tumour cells and associated stromal cells to generate a favourable microenvironment for T-cell lymphoma growth.

Genetically modified mouse models in cancer studies

Genetically modified animals represent a resource of immense potential for cancer research. Classically, genetic modifications in mice were obtained through selected breeding experiments or treatments with powerful carcinogens capable of inducing random mutagenesis. A new era began in the early 1980s when genetic modifications by inserting foreign DNA genes into the cells of an animal allowed for the development of transgenic mice. Since that moment, genetic modifications have been able to be made in a predetermined way. Gene targeting emerged later as a method of in vivo mutagenesis whereby the sequence of a predetermined gene is selectively modified within an intact cell. In this review we focus on how genetically modified mice can be created to study tumour development, and how these models have contributed to an understanding of the genetic alterations involved in human cancer. We also discuss the strengths and weaknesses of the different mouse models for identifying cancer genes, and understanding the consequences of their alterations in order to obtain the maximum benefit for cancer patients (AU)

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Radon exposure in uranium mining industry vs. exposure in tourist caves.

There is a fairly general consensus among health physicists and radiation professionals that exposure to radon progeny is the largest and most variable contribution to the population's exposure to natural sources of radiation. However, this exposure is the subject of continuing debate concerning the validity of risk assessment and recommendations on how to act in radon-prone areas. The purpose of this contribution is to situate the radon issue in Spain in two very different settings. The first is a uranium mining industry located in Saelices el Chico (Salamanca), which is under strict control of the Spanish Nuclear Safety Council (CSN). We have measured radon concentrations in different workplaces in this mine over a five-year period. The second setting comprises four tourist caves, three of which are located in the province of Cantabria and the fourth on the Canary Island of Lanzarote. These caves are not subject to any administrative control of radiation exposure. Measured air 222Rn concentrations were used to estimate annual effective doses due to radon inhalation in the two settings, and dose values were found to be from 2 to 10 times lower in the uranium mine than in the tourist caves. These results were analysed in the context of the new European Basic Safety Standards Directive (EU-BSS, 1996).

Population dose in the vicinity of old Spanish uranium mines.

Regional surveys were conducted to determine exposure to natural sources of radiation for people in the vicinity of old Spanish uranium mines. The surveys evaluated indoor radon concentrations and outdoor and indoor external gamma dose rates. Indoor radon concentrations were measured in 222 dwellings by means of nuclear track-etched detectors. The terrestrial gamma ray dose rate was measured outdoors and indoors at a total of 256 points and 115 points, respectively. Estimates mean annual effective doses for the six areas studied ranged from 3.2 to 5.1 mSv per year, which is between 1.2 and 2 times higher than the average national value.

Natural radiation exposure in the vicinity of Spanish nuclear power stations.

Nationwide and regional surveys have been conducted to evaluate natural radiation exposure of people in the vicinity of the Spanish nuclear power stations. In these surveys, indoor radon, external gamma dose rates outdoors and indoors and radioactivity in soils were measured. Measurements of indoor radon concentrations were performed in 214 dwellings by using nuclear track-etched detectors. External exposure from terrestrial gamma rays outdoors and indoors were measured in a total of 596 points. Radioactivity in soil samples collected at 293 sampling sites are also reported in this paper. By taking into account all sources of natural radiation exposure, mean annual effective doses to the population in the surroundings of the six Spanish nuclear power stations have been estimated and compared with those coming from their normal operation.

[The incidence of the antiphospholipid syndrome in the clinical and biological manifestations of systemic lupus erythematosus]. / Incidencia del síndrome antifosfolípido en las manifestaciones clínicas y biológicas del lupus eritematoso sistémico.

In the present investigation a study was made on the incidence of antiphospholipid syndrome (APS) on clinical and biological manifestations in a series or 32 patients (28 females and 4 males with a mean age of 25 years) diagnosed of SLE (ARA criteria) and APS (Harris criteria) compared with a group of 25 patients (19 females and 6 males with a mean age of 38 years) diagnosed of SLE without APS. This entails a selection from 124 patients diagnosed of SLE, and an incidence of 25.8% and 9.7% for ACA and LA, respectively. After a clinical protocol was filled, a complete immunological profile was obtained, with lymphocyte subsets, IL-2 receptor, coagulation study, isotype determination for anticardiolipin antibody (ACA), lupus anticoagulant (LA), serology for syphilis and imaging diagnostic techniques. Comparative results, with an statistic assessment, are shown in tables. It is concluded that SLE + APS population can be considered as definite for a peculiar SLE subtype.

[The potability of the water in a region with a high level of natural radiation]. / Potabilidad del agua en una región de alto nivel de radiación natural.

BACKGROUND: The recent Spanish legislation on drinkable waters for public use includes a paragraph establishing the requirements to be fulfilled by waters in relation with their radioactivity and the methods to be used to measure it. As water radioactivity depends on the radioactive content of the grounds and rocks where it flows, it is possible to expect high levels in those zones whose characteristic is their high level of natural radiation. METHODS: For this reason, we have organized two measurement campaigns with the objective of characterizing the drinkable waters in an Spanish area, where the radioactive elements concentration in the ground is high. The methodology used is as described in legislation, using a low-bottomed proportional counter. RESULTS: The results we have obtained indicate that the zone, where measurements have been made, shows lower radioactivity levels than the legally established limits, nevertheless, at same time, there appear several points, where the radioactivity levels are high, showing values exceeding in great measure the legal limit for drinkable waters. CONCLUSIONS: With the results, we have obtained, its seems necessary that a greater attention is paid to drinkable waters in those points, where the radioactivity levels are high including corrective measures.